The present invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Thus the invention provides compounds of formula (I) which are agonists at the adenosine A1 receptor. 
wherein R2 represents C1-3alkyl, halogen or hydrogen;
R3 represents straight or branched alkyl group of 1-6 carbon atoms;
R1 represents a group selected from
(1) -(alk)n-(C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group being optionally substituted by one or more substituents selected from OH, halogen, xe2x80x94(C1-3) alkoxy, wherein (alk) represents C1-3alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of xe2x80x94(C1-3)alkyl, xe2x80x94CO2xe2x80x94(C1-4) alkyl, xe2x80x94CO(C1-3alkyl), xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3alkyl), CONRaRb (wherein Ra and Rb independently represent H or C1-3alkyl) or xe2x95x90O, and where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (xe2x95x90O)n where n is 1 or 2.
(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(xe2x95x90O)n, (where n is 0, 1 or 2) or N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy or NRaRb wherein Ra and Rb both represent C1-3alkyl or hydrogen.
(4) a fused bicyclic aromatic ring 
xe2x80x83wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by xe2x80x94CO2 (C1-3alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, xe2x80x94SO3H, -(alk)nOH, -(alk)n-cyano, xe2x80x94(O)nxe2x80x94C1-6-alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, xe2x80x94(O)m-(alk)nxe2x80x94CO2Rc, -(alkn) xe2x80x94CONRcRd, -(alk)nxe2x80x94CORc, -(alk)nxe2x80x94SORe, -(alk)nxe2x80x94SO2Re, -(alk)nSO2NRcRd, -(alk)nORc, -(alk)n(CO)mNHSO2Re, -(alk)nxe2x80x94NHCORc, -(alk)nxe2x80x94NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NRcRd.
Rc and Rd may each independently represent hydrogen, or C1-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.
Re represents C1-3alkyl;
With the proviso that, when R3 represents C1-6 alkyl, R2 represents C1-3 alkyl, R1 cannot represent phenyl optionally substituted by one or more substituents selected from halogen, C1-3alkyl, trifluoromethyl, nitro, cyano, xe2x80x94CO2Rc, xe2x80x94CONRcRd, xe2x80x94CORc, xe2x80x94SORe, xe2x80x94SO2Re, xe2x80x94SO3H, xe2x80x94SO2NRcRd, xe2x80x94ORc, xe2x80x94NHSO2Re, xe2x80x94NHCORc and xe2x80x94NRcRd;
and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
Conveniently, the adenosine A1 agonists of general formula (I) above exhibit greater activity at the adenosine receptor than the other adenosine receptor subtypes, particularly A3. More preferably the compounds exhibit little or no activity at the adenosine A3 receptor.
It will be appreciated that wherein R1 and/or R2 in compounds of formula (I) contain one or more asymmetric carbon atoms the invention includes all diastereoisomers of compounds of formula (I) and mixtures thereof. Otherwise the stereochemical configuration of compounds of the invention is as depicted in formula (I) above.
As used herein, the term xe2x80x9calkylxe2x80x9d means a straight or branched chain alkyl group. Examples of suitable alkyl groups within R1 and R2 include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl and 2,2-dimethylpropyl.
As used herein, the term xe2x80x9cC2-6alkenylxe2x80x9d means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms. Allyl represents an example of a suitable C2-6alkenyl group.
As used herein the term xe2x80x9calkylenexe2x80x9d means a straight or branched chain alkylene group containing 1 to 6 carbon atoms e.g. methylene.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
By aliphatic heterocyclic group is meant a cyclic group of 4-6 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen or sulfur. This group may optionally be substituted as defined hereinabove.
The term heterocyclic aromatic group refers to an aromatic mono or bicyclic ring system comprising from 5 to 10 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur, which ring system may optionally be substituted as defined hereinabove.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. A particularly suitable pharmaceutically acceptable salt of the compounds of formula (I) is the hydrochloride salt. Other acids such as oxalic, while not, in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. The solvates may be, for example, hydrates.
R3 preferably represents a C1-3 alkyl group especially a methyl or ethyl group more preferably methyl.
R2 preferably represents hydrogen, methyl or halogen, more preferably hydrogen or methyl.
Conveniently, R1 may represent (alk)n- C5-7 cycloalkyl, including bridged cycloalkyl wherein n is 0 or 1 and the said cycloalkyl is either substituted by at least one substituent selected from halogen, particularly fluorine, xe2x80x94(C1-3) alkoxy, particularly methoxy and OH or is unsubstituted. Preferably, when substituted the substituent is fluorine and, the cycloalkyl is mono-substituted. Preferably, n represents zero.
Alternatively R1 may represent a substituted or unsubstituted aliphatic heterocyclic group, which when substituted, the substitutent being selected from the group consisting Of C1-3alkyl, xe2x80x94(CO2) xe2x80x94(C1-4)alkyl, xe2x95x90O, xe2x80x94COxe2x80x94(C1-3)alkyl, xe2x80x94S(xe2x95x90O)nxe2x80x94(C1-3)alkyl (where n is 1 or 2), CONRaRb wherein Ra and Rb are defined herein above, and when there is a heteroatom S in the ring, this S is optionally substituted by (xe2x95x90O)n where n is 1 or 2. More preferably the substituents are xe2x80x94CO2C(1-4)alkyl or methyl.
Conveniently the aliphatic heterocyclic group is unsubstituted or when the substituent is xe2x80x94CO2(C1-4)alkyl the heteroatom is N and the substituent is directly attached to said ring nitrogen atom.
Preferably the heterocyclic ring is 6 membered and more preferably contains only one N, O or S heteroatom.
Alternatively, R1 may represent a straight or branched alkyl of 1-6 carbon atoms optionally including at least one S (xe2x95x90O)2, O or N substituted in the chain. The alkyl group conveniently may be further substituted by at least one group selected from OH, phenyl and fluorine or is unsubstututed.
Alternatively R1 may represent a phenyl group which is substituted by one or more substituents selected from OH, halogen, (O)m (alk)n CO2Rc, and -(alk)nOH. Preferably the phenyl is disubstituted in the 2,4 positions. Preferably both substituents are halogen more particularly, fluorine and chlorine. For example, a particularly preferred combination is 2- fluoro and 4- chloro.
Alternatively R1 represents a phenyl group substituted by a 5-tetrazolyl group, this group itself optionally substituted by C1-3alkyl.
Alternatively R1 represents a fused group. 
wherein B represents a furan ring, said furan ring being optionally substituted by xe2x80x94CO2(C1-3)alkyl more preferably in the 2 position.
It is to be understood that the present invention covers all combinations of particular and preferred groups mentioned above.
Particular compounds according to the invention include:
5xe2x80x2-O-Methyl-N-(tetrahydro-furan-3R-yl)-adenosine
N-(2R-Hydroxy-(R)-cyclopentyl)-5xe2x80x2-O-methyl-adenosine
5xe2x80x2-O-Methyl-N-(tetrahydro-pyran4-yl)-adenosine
N-(2S-Methoxy-(S)-cyclopentyl)-5xe2x80x2-O-methyl-adenosine
5xe2x80x2-O-Methyl-N-(2S-methyl-tetrahydro-furan-3R-yl)-adenosine
N-(3-Chloro4-hydroxy-phenyl)-5xe2x80x2-O-methyl-adenosine
5xe2x80x2-O-Methyl-N-(1R-methyl-2-phenyl-ethyl)-adenosine
N-tert-Butyl-5xe2x80x2-O-methyl-adenosine
N-(2S-Fluoro-(S)-cyclopentyl)-5xe2x80x2-O-methyl-adenosine
N-(2, 3-Dihydroxy-propylamino)-5xe2x80x2-O-methyl-adenosine
N-rel-[(1S,4R)-Bicyclo[2.2.1]hept-2R-yl]-5xe2x80x2-O-methyl-adenosine
4-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-9H-purin-6-ylamino]-piperidine-1-carboxylic acid ethyl ester
5xe2x80x2-O-Methyl-N-[4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-adenosine
3-{4-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-9H-purin-6-ylamino]-phenyl}-(E)-acrylic acid
N-(4-Hydroxymethyl-phenyl)-5xe2x80x2-O-methyl-adenosine
{4-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-9H-purin-6-ylaminol]-phenoxy}acetic acid
5-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-9H-purin-6-ylaminol]-benzofuran-2-carboxylic acid methyl ester
5xe2x80x2-O-Methyl-N-(tetrahydro-thiopyran4-yl)-adenosine
N-rel-[(1R,5R)-Bicyclo[3.2.0]hept-6S-yl]-5xe2x80x2-O-methyl-adenosine
4-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-2-methyl-9H-purin-6-ylamino]-piperidin-2-one
5xe2x80x2-O-Methyl-N-(1S-methoxymethyl-2-methyl-propyl)-adenosine
N-(2-Hydroxy-1R-methyl-ethyl)-5xe2x80x2-O-methyl-adenosine
N-(2-Fluoro-1R-methyl-ethyl)-5xe2x80x2-O-methyl-adenosine
N-(1S-Fluoromethyl-2-methoxy-ethyl)-5xe2x80x2-O-methyl-adenosine
N-(3-Amino-propyl)-5xe2x80x2-O-methyl-adenosine
2-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-2-methyl-9H-purin-6-ylamino]-acid methylamide
N-Cyclopentyl-2-methyl-5xe2x80x2-O-methyl-adenosine
N-Cyclopropylmethyl-2-methyl-5xe2x80x2-O-methyl-adenosine
Compounds according to the invention have applicability as inhibitors of lipolysis i.e. they decrease plasma free fatty acid concentrations. The compounds may thus be used in the treatment of hyperlipidaemias. Furthermore, as a consequence of their anti-lipolytic activity, the compounds have the ability to lower elevated blood glucose, insulin and ketone body levels and therefore may be of value in the therapy of diabetes. Since anti-lipolytic agents have hypolipidaemic and hypofibrinogenaemic activity, the compounds may also show anti-atherosclerotic activity. The anti-lipolytic activity of compounds of the invention has been demonstrated by their ability to lower the concentration of non-esterified fatty acids (NEFA) in starved rats dosed orally according to the method described by P. Strong et al. in Clinical Science (1993), 84, 663-669.
In addition to their anti-lipolytic effect, the compounds of the invention may independently affect cardiac function by reducing heart rate and conduction. The compounds may thus be used in the therapy of a number of cardiovascular disorders, for example cardiac arrythmias, particularly following myocardial infarction, and angina.
Furthermore, the compounds of the invention are useful as cardioprotective agents, having applicability in the treatment of ischaemic heart disease. As used herein the term xe2x80x9cischaemic heart diseasexe2x80x9d includes damage associated with both myocardial ischaemia and reperfusion, for example, associated with coronary artery bypass grafting (CABG), percutaneous translumenal coronary angioplasty (PTCA), cardioplegia, acute myocardial infarction, thrombolysis, stable and unstable angina and cardiac surgery including in particular cardiac transplantation. The compounds of the invention additionally are useful for treating ischaemic damage to other organs. The compounds of the invention may also be valuable in the treatment of other disorders arising as a result of widespread atheromatous disease, for example, peripheral vascular disease (PVD) and stroke.
The compounds may also inhibit renin release and thus be of use in the therapy of hypertension and heart failure. The compounds may also be useful as CNS agents (e.g. as hypnotics, sedatives, analgesics and/or anti-convulsants particularly finding use in the treatment of epilepsy).
In addition, the compounds of the invention may find use in the treatment of sleep apnoea.
The compound of formula (I) and pharmaceutically acceptable acid addition salts thereof are useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically of a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compound of formula (I) and its pharmaceutically acceptable acid addition salts may be used as a preemptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, neuropathies associated with diabetes, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compound of formula (I) may also be used in the treatment or prevention of pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders (eg IBS), non cardiac chest pain and non ulcer dyspepsia.
Accordingly, the invention provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or whereby the therapy involves the treatment of ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering from a CNS disorder, sleep apnoea or pain.
In a further aspect, the invention provides a method of treatment of a human or animal subject suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering a CNS disorder or suffering from sleep apnoea or suffering pain, which method comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In respect of the above mentioned ischaemic treatment, it has been found that according to a particularly unexpected aspect of the present invention, not only does administration of a compound of formula (I) prior to ischaemia provide protection against myocardial infarction, but protection is also afforded if the compound of formula (I) is administered after the ischaemic event and before reperfusion. This means that the methods of the present invention are applicable not only where ischaemia is planned or expected, for example in cardiac surgery, but also in cases of sudden or unexpected ischaemia, for example in heart attack and unstable angina.
It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.
In yet a further aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutical carrier and/or excipient.
In another aspect, the invention provides a pharmaceutical composition comprising, as active ingredient, at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutical carrier and/or excipient for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering from a CNS disorder, sleep apnoea or pain.
There is further provided by the present invention a process of preparing a pharmaceutical composition, which process comprises mixing at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier and/or excipient.
Compositions according to the invention may be formulated for topical, oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The compositions may be adapted for sustained release.
For topical administration, the pharmaceutical composition may be conveniently given in the form of a transdermal patch.
Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents (e.g. mannitol) as appropriate.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (I) may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Altematively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The compounds of formula (I) may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
A proposed dose of the compounds of the invention for administration to man (of approximately 70 kg body weight) is 1 mg to 2 g, preferably 1 mg to 100 mg, of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient. The dosage will also depend on the route of administration.
In a yet further aspect the invention also provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease (PVD) or stroke, or which patient is suffering from a CNS disorder, sleep apnoea or pain.
The compounds of formula (I) and physiologically acceptable salts or solvates thereof may be prepared by the processes described hereinafter, said processes constituting a further aspect of the invention. In the following description, the groups R1, R2 and R3 are as defined for compounds of formula (I) unless otherwise stated.
According to a first general process (A), a compound of formula (I) may be prepared by reacting a compound of formula (II). 
wherein, L represents a leaving group such as a halogen atom (e.g. a chlorine atom) and P1 and P2 represent hydrogen or a suitable protecting group (e.g. acetyl). with a compound of formula R1NH2 or a salt thereof, under basic conditions.
Compounds of formula (II) may be used to produce compounds of formula (I) directly by reaction with the group R1NH2 either in the absence or presence of a solvent such as an alcohol (e.g. a lower alkanol such as isopropanol, t-butanol or 3-pentanol), an ether (e.g. tetrahydrofuran or dioxan), a substituted amide (e.g. dimethylformamide), a halogenated hydrocarbon (e.g. chloroform) or acetonitrile, preferably at an elevated temperature (e.g. up to the reflux temperature of the solvent), in the presence of a suitable acid scavanger, for example, inorganic bases such as sodium or potassium carbonate, or organic bases such as triethylamine, diisopropylethylamine or pyridine.
This reaction may be preceded or followed where appropriate by in situ removal of the P1 and P2 protecting groups. For example when P1 and P2 represent acetyl, this may be effected with an amine such as ammonia or tert-butylamine in a solvent such as methanol.
Compounds of formula (II) may be prepared by the reaction of a compound of formula (III). 
wherein p3 represents a suitable protecting group for example C1-3alkyl or acetyl, and P1, P2 and R3 are as defined above, with a compound of formula (IV) 
wherein L and R2 are as defined above.
The reaction is conveniently carried out in a suitable solvent, such as acetonitrile in the presence of a silylating agent such as trimethylsilyl trifluoromethane sulfonate and a base such as diazabicyclo [5.4.0]undec-7-ene (DBU). Alternatively the compound of formula (IV) may first be silylated with a suitable silylating agent e.g. hexamethyidisilazane followed by reaction of the silylated intermediate with a compound of formula (III) and a suitable Lewis acid, e.g. trimethylsilyl trifluoromethane sulfonate in a suitable solvent such as acetronitrile.
Compounds of formula (IV) are either known in the art or may be prepared from known compounds using methods analogous to those used to prepare the known compounds of formula (IV).
Compounds of formula (III) may be prepared from alternative protected compounds by replacement of the alternate protecting groups with P1 and P2, for example when P1 and P2 represent acetyl, compounds of formula (III) may be prepared from compounds of formula (V), wherein P4 and P5 represent C1-3 alkyl and P3 is as defined above, by acid catalysed removal of the alkylidine protecting group, e.g. with hydrogen chloride in methanol, followed by in situ acylation for example with acetic anhydride in the presence of a base such as pyridine, in a solvent such as dichloromethane. 
Compounds of formula (V) are known compounds or prepared by methods analogous to those used in the art to prepare the known compounds of formula V. It will be appreciated by a skilled person that the acetyl group in any of the compounds above could be replaced with any suitable protecting group, for example, other esters.
By analogous methods, compounds of formula (I) or (II) may also be prepared from compounds wherein alkylidine groups defined by P4 and P5 replace P1 an P2. This reaction represents an exchange of one protecting group for another and such reactions will be apparent to a person skilled in the art.
A further process (B) comprises converting a compound of formula (I) into a different compound of formula (I) by modifying the R1, R2 or R3 group therein.
Certain compounds of formulae (II), (III), (IV), and (V) are novel intermediates and form a further aspect of the present invention.
Compounds of the formula R1NH2 are either known compounds or may be prepared from known compounds using conventional procedures.
Specific optical isomers of a compound of formula (I) may be obtained by conventional methods for example, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or where appropriate by separation of a mixture of isomers of a compound of formula (I) by conventional means e.g by fractional crystallisation or chromatography.
In the general processes described above, the compound of formula (I) obtained may be in the form of a salt, conveniently into the form of a pharmaceutically acceptable salt. Where desired, such salts may be converted into the corresponding free bases using conventional methods.
Pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be prepared by reacting a compound of formula (I) with an appropriate acid in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol (e.g. methanol, ethanol or isopropanol). Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of a compound of formula (I) with a suitable base. Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts of the compounds of formula (I), using conventional methods.